NM_000179.3(MSH6):c.3513_3514del (p.Asp1171fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000162609.9

Allele description [Variation Report for NM_000179.3(MSH6):c.3513_3514del (p.Asp1171fs)]

NM_000179.3(MSH6):c.3513_3514del (p.Asp1171fs)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3513_3514del (p.Asp1171fs)

HGVS:

NC_000002.11:g.48032122_48032123del
NC_000002.12:g.47804984_47804985del
NG_007111.1:g.26838_26839del
NG_008397.1:g.105692_105693del
NM_000179.3:c.3513_3514delMANE SELECT
NM_001281492.2:c.3123_3124del
NM_001281493.2:c.2607_2608del
NM_001281494.2:c.2607_2608del
NP_000170.1:p.Asp1171fs
NP_001268421.1:p.Asp1041fs
NP_001268422.1:p.Asp869fs
NP_001268423.1:p.Asp869fs
LRG_219:g.26838_26839del
NC_000002.11:g.48032122_48032123del
NC_000002.11:g.48032123_48032124del
NC_000002.11:g.48032123_48032124delTA
NM_000179.2:c.3513_3514delTA
p.Asp1171Glufs*5
p.Asp1171GlufsX5
p.D1171Efs*5

Protein change:

D1041fs

Links:

dbSNP: rs63750194

NCBI 1000 Genomes Browser:

rs63750194

Molecular consequence:

NM_000179.3:c.3513_3514del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281492.2:c.3123_3124del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281493.2:c.2607_2608del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001281494.2:c.2607_2608del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000213037	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14974087, 24323032, 29107668, 32875559 Citation Link,
SCV001734547	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002528037	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Feb 16, 2022)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 14974087, 20007843, 24323032, 25142776, 20301390 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213037

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 14, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001734547

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 28, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002528037

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Feb 16, 2022)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome.

Dillon JL, Gonzalez JL, DeMars L, Bloch KJ, Tafe LJ.

Hum Pathol. 2017 Dec;70:121-128. doi: 10.1016/j.humpath.2017.10.022. Epub 2017 Oct 28.

PubMed [citation]

PMID:: 29107668

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.

Wokołorczyk D, Kluźniak W, Huzarski T, Gronwald J, Szymiczek A, Rusak B, Stempa K, Gliniewicz K, Kashyap A, Morawska S, Dębniak T, Jakubowska A, Szwiec M, Domagała P, Lubiński J, Narod SA, Akbari MR, Cybulski C; Polish Hereditary Prostate Cancer Consortium..

Int J Cancer. 2020 Nov 15;147(10):2793-2800. doi: 10.1002/ijc.33272. Epub 2020 Sep 11.

PubMed [citation]

PMID:: 32875559

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000213037.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.3513_3514delTA pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a deletion of two nucleotides between positions 3513 and 3514, causing a translational frameshift with a predicted alternate stop codon (p.D1171Efs*5). This alteration was previously reported in a man with ascending colon cancer at 31 years whose tumor demonstrated high microsatellite instability and isolated absence of MSH6 on immunohistochemistry (IHC) (Plaschke J et al. Hum Mutat. 2004 Mar;23(3):285). This alteration was also reported in a woman diagnosed with serous endometrial cancer at 51 years whose tumor demonstrated isolated absence of MSH6 on IHC (Buchanan DD et al. J. Clin. Oncol. 2014 Jan;32(2):90-100). This alteration has been reported in a man diagnosed with colon cancer at age 56 years whose tumor demonstrated microsatellite stability and normal protein expression on IHC (Kraus C et al. Int. J. Cancer. 2015 Mar 15;136(6):E559-68). Additionally, this alteration has been detected in a Polish patient with prostate cancer (Wokoorczyk D et al. Int J Cancer. 2020 11;147:2793-2800). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001734547.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant deletes 2 nucleotides in exon 6 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 29107668, 18301448, 14974087) and in individuals with endometrial or colorectal cancers (PMID: 25142776, 24323032). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002528037.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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